Transcriptional regulation of development and homeostasis in complex eukaryotes, including humans and other mammals, birds, fish, insects, and the like, is controlled by a wide variety of regulatory substances, including steroid and thyroid hormones. These hormones exert potent effects on development and differentiation of phylogenetically diverse organisms. The effects of hormones are mediated by interaction with specific, high affinity binding proteins referred to as receptors.
A number of receptor proteins are known, each specific for steroid hormones [e.g., estrogens (estrogen receptor), progesterones (progesterone receptor), glucocorticoid (glucocorticoid receptor), androgens (androgen receptor), aldosterones (mineralocorticoid receptor), vitamin D (vitamin D receptor)], retinoids (e.g., retinoic acid receptor) or thyroid hormones (e.g., thyroid hormone receptor). Receptor proteins have been found to be distributed throughout the cell population of complex eukaryotes in a tissue specific fashion.
Molecular cloning studies have made it possible to demonstrate that receptors for steroid, retinoid and thyroid hormones are all structurally related and comprise a superfamily of regulatory proteins. These regulatory proteins are capable of modulating specific gene expression in response to hormone stimulation by binding directly to cis-acting elements.
It is known that steroid or thyroid hormones, protected forms thereof, or metabolites thereof, enter cells and bind to the corresponding specific receptor protein, initiating an allosteric alteration of the protein. As a result of this alteration, the complex of receptor and hormone (or metabolite thereof) is capable of binding with high affinity to certain specific sites on chromatin. One of the primary effects of steroid and thyroid hormones is an increase in transcription of a subset of genes in specific cell types.
A number of transcriptional control units which are responsive to members of the steroid/thyroid superfamily of receptors have been identified. These include the mouse mammary tumor virus 5′-long terminal repeat (MTV LTR), responsive to glucocorticoid, aldosterone and androgen hormones; the transcriptional control units for mammalian growth hormone genes, responsive to glucocorticoids, estrogens and thyroid hormones; the transcriptional control units for mammalian prolactin genes and progesterone receptor genes, responsive to estrogens; the transcriptional control units for avian ovalbumin genes, responsive to progesterones; mammalian metallothionein gene transcriptional control units, responsive to glucocorticoids; and mammalian hepatic α2u-globulin gene transcriptional control units, responsive to androgens, estrogens, thyroid hormones, and glucocorticoids.
A major obstacle to further understanding and more widespread use of the various members of the steroid/thyroid superfamily of hormone receptors has been a lack of awareness of the possible interactions of various members of the steroid/thyroid superfamily of hormone receptors, and an understanding of the implications of such interactions on the ability of members of the steroid/thyroid superfamily of hormone receptors to exert transcriptional regulation of various physiological processes.
DNA binding studies on the glucocorticoid receptor (GR) and the estrogen receptor (ER) have indicated that these receptors bind to their hormone response elements (HREs) as homodimeric complexes [see, for example, Kumar and Chambon in Cell 55:145–156 (1988) and Tsi et al., in Cell 55:361–369 (1988)]. However, recent biochemical analysis has revealed that some other receptors (including retinoic acid receptor (RAR), thyroid hormone receptor (TR), and the vitamin D receptor (VDR)) can not efficiently bind to cognate response elements as homodimers, but rather require additional factors present in cell nuclear extracts to achieve high affinity DNA binding [see, for example, Murray and Towle in Mol. Endocrinol. 3:1434–1442 (1989), Glass et al., in Cell 63:729–738 (1990), Liao et al., in Proc. Natl. Acad. Sci. USA 87:9751–9755 (1990), and Yang et al., in Proc. Natl. Acad. Sci. USA 88:3559–3563 (1991)].
Several recent reports have identified members of the retinoid X receptor family (RXR; see, for example, Mangelsdorf et al., in Nature 345:224–229 (1990) and Gene Dev. 6:329–344 (1992), and Leid et al., in Cell 68:377–395 (1992)) as factors that can interact with RAR and potentiate DNA binding by forming a novel RAR/RXR heterodimer [see, for example, Yu et al., in Cell 67:1251–1266 (1991), Kliewer et al., in Nature 355:446–449 (1992), Leid et al., supra, and Zhang et al., in Nature 355:441–446 (1992)]. Interestingly, RAR is not the only receptor with which RXR can interact. In fact, RXR has been found to be capable of heterodimerizing with several other members of the nuclear receptor superfamily, including VDR, TR (see Kliewer, et al., supra) and peroxisome proliferator-activated receptor (PPAR; see, for example, Issemann and Green in Nature 347: 645–650 (1990)).
Although the physiological significance of these interactions remains to be definitively determined, the capability of nuclear receptors to heterodimerize suggests the existence of an elaborate network through which distinct nuclear hormone receptor classes are capable of modulating each other's activity. In addition, the possible existence of other factors that can potentially interact with members of the steroid/thyroid superfamily and potentiate DNA binding by forming novel heteromeric species remains to be determined.